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Primary tumor location as a predictor of survival in patients with RAS wild-type colorectal cancer who receive molecularly targeted drugs as first-line therapy: a multicenter real-world observational study by the Japanese Society for Cancer of the Colon and Rectum

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Abstract

Background

Primary tumor location is considered a predictor of overall survival (OS) in RAS wild-type (WT) metastatic colorectal cancer (mCRC) treated with bevacizumab (BEV) or an anti-epidermal growth factor antibody (cetuximab or panitumumab [CET/PAN]) as first-line molecularly targeted therapy. BEV is recommended for right-sided mCRC and CET/PAN for left-sided mCRC based on post-hoc analyses of clinical trial data, but real-world evidence is lacking.

Methods

We retrospectively collected data of patients who started BEV or CET/PAN plus 5-fluorouracil-based doublet chemotherapy between January 2013 and December 2016 as first-line treatment for RAS WT mCRC at any of 24 Japanese institutions. OS was compared between the BEV and CET/PAN groups according to primary tumor location by Cox multivariate regression analysis in the full cohort and in a propensity score-matched cohort.

Results

In total, 935 patients were enrolled. Median OS was 24.6 months with BEV and 20.9 months with CET/PAN in right-sided mCRC (n = 213; adjusted hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.50–1.06) and 35.7 months and 30.0 months, respectively, in left-sided mCRC (n = 722; adjusted HR 0.92, 95% CI 0.74–1.13). In the propensity score-matched cohort, OS was significantly better in the BEV group than in the CET/PAN group in right-sided mCRC (HR 0.52, 95% CI 0.28–0.96) but was not significantly different in left-sided mCRC (HR 0.78, 95% CI 0.53–1.07).

Conclusion

Real-world data showed that OS was better with BEV than with CET/PAN in right-sided mCRC. However, there was no significant difference in OS in left-sided mCRC.

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References

  1. Benson AB, Venook AP, Al-Hawary MM et al (2021) Colon cancer, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw 19:329–359

    Article  Google Scholar 

  2. Van Cutsem E, Cervantes A, Adam R et al (2016) ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 27:1386–1422

    Article  Google Scholar 

  3. Yoshino T, Arnold D, Taniguchi H et al (2018) Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann Oncol 29:44–70

    Article  CAS  Google Scholar 

  4. Hashiguchi Y, Muro K, Saito Y et al (2020) Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer. Int J Clin Oncol 25:1–42

    Article  Google Scholar 

  5. Heinemann V, von Weikersthal LF, Decker T et al (2014) FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 15:1065–1075

    Article  CAS  Google Scholar 

  6. Venook AP, Niedzwiecki D, Lenz HJ et al (2017) Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA 317:2392–2401

    Article  CAS  Google Scholar 

  7. Stintzing S, Modest DP, Rossius L et al (2016) FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol 17:1426–1434

    Article  CAS  Google Scholar 

  8. Venook AP, Niedzwiecki D, Lenz H-J et al (2014) CALGB/SWOG80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin Oncol 32(15 Suppl):LBA3

    Article  Google Scholar 

  9. Rivera F, Karthaus M, Hecht JR et al (2017) Final analysis of the randomised PEAK trial: overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma. Int J Colorectal Dis 32:1179–1190

    Article  Google Scholar 

  10. Holch JW, Ricard I, Stintzing S et al (2017) The relevance of primary tumour location in patients with metastatic colorectal cancer: a meta-analysis of first-line clinical trials. Eur J Cancer 70:87–98

    Article  Google Scholar 

  11. Arnold D, Lueza B, Douillard JY et al (2017) Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol 28:1713–1729

    Article  CAS  Google Scholar 

  12. Petrelli F, Tomasello G, Borgonovo K et al (2017) Prognostic survival associated with left-sided vs right-sided colon cancer: a systematic review and meta-analysis. JAMA Oncol 3:211–219

    Article  Google Scholar 

  13. Tejpar S, Stintzing S, Ciardiello F et al (2017) Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol 3:194–201

    Article  Google Scholar 

  14. You XH, Jiang YH, Fang Z et al (2020) Chemotherapy plus bevacizumab as an optimal first-line therapeutic treatment for patients with right-sided metastatic colon cancer: a meta-analysis of first-line clinical trials. ESMO Open 5:e00065

    Article  Google Scholar 

  15. Cremolini C, Loupakis F, Ruzzo A et al (2010) Predictors of benefit in colorectal cancer treated with cetuximab: are we getting “Lost in TranslationAL”? J Clin Oncol 28:e173–e174 (author reply e175–e176)

    Article  Google Scholar 

  16. Hutajulu SH, Paramita DK, Santoso J et al (2018) Correlation between vascular endothelial growth factor—a expression and tumor location and invasion in patients with colorectal cancer. J Gastrointest Oncol 9:1099–1108

    Article  Google Scholar 

  17. Bendardaf R, Buhmeida A, Hilska M et al (2008) VEGF-1 expression in colorectal cancer is associated with disease localization, stage, and long-term disease-specific survival. Anticancer Res 28:3865–3870

    PubMed  Google Scholar 

  18. Missiaglia E, Jacobs B, D’Ario G et al (2014) Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann Oncol 25:1995–2001

    Article  CAS  Google Scholar 

  19. Aggarwal H, Sheffield KM, Li L et al (2020) Primary tumor location and survival in colorectal cancer: a retrospective cohort study. World J Gastrointest Oncol 12:405–423

    Article  Google Scholar 

  20. Marques RP, Godinho AR, Heudtlass P et al (2020) Cetuximab versus bevacizumab in metastatic colorectal cancer: a comparative effectiveness study. J Cancer Res Clin Oncol 146:1321–1334

    Article  CAS  Google Scholar 

  21. Sagawa T, Sato Y, Hirakawa M et al (2020) Clinical impact of primary tumour location, early tumour shrinkage, and depth of response in the treatment of metastatic colorectal cancer with first-line chemotherapy plus cetuximab or bevacizumab. Sci Rep 10:19815

    Article  CAS  Google Scholar 

  22. Grassadonia A, Di Marino P, Ficorella C et al (2019) Impact of primary tumor location in patients with RAS wild-type metastatic colon cancer treated with first-line chemotherapy plus anti-EGFR or anti-VEGF monoclonal antibodies: a retrospective multicenter study. J Cancer 10:5926–5934

    Article  CAS  Google Scholar 

  23. Bennouna J, Sastre J, Arnold D et al (2013) Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 14:29–37

    Article  CAS  Google Scholar 

  24. Van Cutsem E, Tabernero J, Lakomy R et al (2012) Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 30:3499–3506

    Article  Google Scholar 

  25. Tabernero J, Yoshino T, Cohn AL et al (2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16:499–508

    Article  CAS  Google Scholar 

  26. Rowland A, Dias MM, Wiese MD et al (2015) Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br J Cancer 112:1888–1894

    Article  CAS  Google Scholar 

  27. Bylsma LC, Gillezeau C, Garawin TA et al (2020) Prevalence of RAS and BRAF mutations in metastatic colorectal cancer patients by tumor sidedness: a systematic review and meta-analysis. Cancer Med 9:1044–1057

    Article  Google Scholar 

  28. Yoshino T, Uetake H, Tsuchihara K et al (2017) Rationale for and design of the PARADIGM study: randomized phase III study of mFOLFOX6 plus bevacizumab or panitumumab in chemotherapy-naïve patients with RAS (KRAS/NRAS) wild-type, metastatic colorectal cancer. Clin Colorectal Cancer 16:158–163

    Article  Google Scholar 

Download references

Acknowledgements

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Takahiko Ito & Atsuo Takashima

  2. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan

    Takahiko Ito

  3. Department of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumicho, Suntougun, Shizuoka, 411-8777, Japan

    Kentaro Yamazaki

  4. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan

    Hiroki Yukami

  5. Osaka Medical and Pharmaceutical University Hospital, 2-7 Daigaku-machi, Takatsuki, Osaka, 569-8686, Japan

    Hiroki Yukami & Masahiro Goto

  6. National Hospital Organization Disaster Medical Center, 3256 Midori-cho, Tachikawa, Tokyo, 190-0014, Japan

    Hiroyuki Uetake

  7. Hyogo Cancer Center, 13-70 Kitaouji-cho, Akashi, Hyogo, 673-8558, Japan

    Masahiro Tsuda

  8. Department of Gastroenterological Surgery, Yamagata Prefectural Central Hospital, 1800 Aoyagi, Yamagata, 990-2292, Japan

    Takeshi Suto

  9. Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Toshikazu Moriwaki

  10. Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan

    Naotoshi Sugimoto

  11. Department of Gastrointestinal Surgery, Gunma Prefectural Cancer Center, 617-1 Takabayashi, Ota, Gunma, 373-8550, Japan

    Hitoshi Ojima

  12. Department of Gastroenterological Surgery, Niigata Cancer Center Hospital, 2-15-3 Kawagichi-cho, Chuo-ku, Niigata, Niigata, 951-8566, Japan

    Yasumasa Takii

  13. Department of Medical Oncology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan

    Hisateru Yasui

  14. Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, Fukuoka, 811-1395, Japan

    Taito Esaki

  15. Kagawa University Faculty of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan

    Akihito Tsuji

  16. Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan

    Masayuki Saruta

  17. Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan

    Satoshi Otsu

  18. Division of Clinical Oncology, Hiroshima Prefectural Hospital, 1-5-54 Ujinakanda, Minami-ku, Hiroshima, Hiroshima, 734-8530, Japan

    Katsunori Shinozaki

  19. Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan

    Toshiyoshi Fujiwara

  20. Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-0014, Japan

    Takao Tamura

  21. Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka, 812-8582, Japan

    Eishi Baba

  22. Kanagawa Cancer Center, Gastrointestinal Surgery, 2-3-2 Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8512, Japan

    Manabu Shiozawa

  23. Chiba Cancer Center, 666-2 Nitona-cho, Chuo-ku, Chiba, Chiba, 260-8717, Japan

    Tadamichi Denda

  24. Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan

    Hideki Ueno

  25. Keio University Hospital, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Kengo Nagashima

  26. Kochi Health Science Center, 2125-1 Ike, Kochi, Kochi, 781-8555, Japan

    Yasuhiro Shimada

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  1. Takahiko Ito
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Corresponding author

Correspondence to Atsuo Takashima.

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Conflict of interest

AT has received personal fees from Eli Lilly, personal fees from Taiho Pharmaceutical, grants and personal fees from Ono Pharmaceutical, personal fees from Chugai Pharma, grants and personal fees from Takeda, personal fees from Merck Serono, grants from Merck Sharp & Dohme, grants from Eisai, grants from Bayer Yakuhin, grants from Bristol Myers Squibb, all outside the submitted work. HY has received honoraria from Taiho Pharmaceutical, Chugai Pharma, Eli Lilly Japan, Merk Biopharma, Yakult Honsha, Bayer Yakuhin, and Takeda Pharmaceutical, all outside the submitted work. TE has received grants from MSD, Novartis, Ono, Astellas, Astellas Amgen Biopharma, BeiGene, Ignyta, Array BioPharma, Merck Serono, and Dainippon Sumitomo as well as honoraria from Chugai, all outside the submitted work. TT received personal fees from Daiichi Sankyo Co., Ltd. as well as grants from Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., BeiGene Co., Ltd., and Ono Pharmaceutical Co., Ltd., all outside the submitted work. EB received research funding from Ono, Merck Sharp & Dohme, Eisai, Taiho, Bayer, Eli Lilly, Chugai, and Daichi-Sankyo as well as honoraria for lecture and advisory roles from Ono, Chugai, Taiho, Tsumura, Eli Lilly, Merck Sharp & Dohme, Sanofi, Miyarisan, Daiichi-Sankyo, AstraZeneca, Astellas, all outside the submitted work. TD received personal fees from Sysmex, Ono Pharmaceutical, and Sawai, all outside the submitted work. HU received research funding for his institution from Chugai and Takeda pharmaceutical companies, both outside the submitted work. TI, HS, HY, HU, MT, TS, HO, YT, AT, MG MSa, SO, KS, TF, MSh, KN, and YS declare no competing interests.

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Ito, T., Takashima, A., Yamazaki, K. et al. Primary tumor location as a predictor of survival in patients with RAS wild-type colorectal cancer who receive molecularly targeted drugs as first-line therapy: a multicenter real-world observational study by the Japanese Society for Cancer of the Colon and Rectum. Int J Clin Oncol 27, 1450–1458 (2022). https://doi.org/10.1007/s10147-022-02208-7

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